Structural underpinnings and long-term effects of resilience in Parkinson’s disease

Resilience in neuroscience generally refers to an individual’s capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer’s disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson’s disease is limited. Our study involved 151 Parkinson’s patients from the Parkinson’s Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson’s patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.

Further, the correlation analysis between the tremor sub-score and the putaminal dopamine transporter signal did not reach the significance threshold.This supports previous evidence that the tremor-related items of the MDS-UPDRS-III score are not a direct cause of the dopaminergic cell loss.
3) The regression model predicting the less affected axial LAR MDS-UPDRS-III subscore by the contralateral putaminal dopamine transporter signal showed a better model fit compared to the one modelling the more affected sub-score.
less affected axial LAR sub-score ~ contralateral putaminal signal, age, sex (F(3,147)=11.4, p<0.001, r=.43, r²=.19) vs. more affected axial LAR sub-score ~ contralateral putaminal signal, age, sex (F(3,147) =8.0, p<0.001, r=.38, r²=.14)Both regression models were significant, but a better model fit was observed for the model predicting the less affected body side.Closer investigations revealed a flooring effect regarding the correlation between the more affected axial LAR subscore and contralateral putaminal dopamine transporter signal (Supplementary Figure 1).Ceiling and flooring effects are both critical for the application of the residual approach, given the range of the predictor is limited (Elman et al., 2022).
In summary, considering the difference in model fit and the described flooring effect, the closest association between dopamine transporter signal and MDS-UPDRS-III score was achieved with the less affected MDS-UPDRS-III sub-score containing axial and LAR items and the contralateral putaminal dopamine transporter signal.

Association between resilience and daily physical activity
Seven partial Spearman correlation analyses between Physical Activity Scales of the Elderly (PASE) of different assessment dates (every full year from year 1 till year 7) and the baseline resilience estimates were performed (Supplementary Figure 2).All showed the same trend, namely higher resilience estimates (negative residual values) being associated with greater physical activity scores.While this significant association validated the derived resilience estimates for the year one correlation, significant correlations at later time points indicate that the resilience estimates might have a predictive value for future physical activity levels.

Linear mixed model, including cognitive function and medication information
Including the levodopa equivalent daily dose (LEDD) and MoCA score did not change the results of the time*residual category interaction term or any other fixed parameter in the mixed model analysis.While the baseline MoCA score did not significantly contribute to the models (p>0.05), the LEDD was significant when predicting the total MDS-UPDRS-III score or the more affected axial limb-akinetic-rigid sub-score (for test statistic and p-values see Supplementary Table 2).

Survival analysis -Time until onset of levodopa-induced dyskinesia
Six Kaplan-Meier survival analyses, regarding the time until onset of levodopa-induced dyskinesia based on either MDS-UPDRS-III or -IV (motor complication) assessments over three different time intervals, were performed.The analyses revealed a trend of the curves of the higher resilience group laying above those of the low resilience group, indicating that high resilience patients experience longer intervals until the onset of levodopa-induced dyskinesia.However, the difference in survival time did not reach significance (p<0.05).Different time intervals (84, 102, 156 months), information sources (MDS-UPDRS-III or -IV score), or residual levels (residual split at 0SD, +/-0.5SD,+/-1SD) did not influence the result of the analyses (for survival curves and associated test statistics, see Supplementary Figure 4).

MDS-UPDRS-III sub-scores
The hierarchical hypothesis testing, as illustrated in Figure 7

Hypothesis
The first hypothesis claims that the putaminal dopamine transporter signal is closer associated with the MDS-UPDRS-III score than the dopamine transporter signal of the caudate nucleus.To test this hypothesis, the correlation coefficients of the correlations between the mean dopamine transporter signal of the putamen, or caudate nucleus with the entire MDS-UPDRS-III score, were compared.

Hypothesis
The second hypothesis claims that the axial and LAR MDS-UPDRS-III sub-scores are closer associated with the dopamine transporter signal of the putamen than the tremor sub-score.To test this hypothesis, the correlation coefficients of the correlation between 1) axial, or 2) LAR, or 3) tremor sub-scores with the dopamine transporter signal of the mean putamen were compared.

Hypothesis:
The third hypothesis considers the laterality of the dopaminergic degeneration and laterality of symptom onset.Considering the crossing of the fibre bundles, the more affected bodyside should be located contralateral to the more affected hemisphere, while in this case, the less affected hemisphere should be located ipsilateral.
Considering this anatomical basis and previous studies, anatomically ipsilateral correlations were considered to be less meaningful in a biological sense than anatomically contralateral ones.Hypothesis three claims that the less affected bodyside and contralateral hemisphere are more closely associated than the more affected bodyside and contralateral hemisphere.To test this hypothesis, we compared two regression models, predicting either the less or more affected MDS-UPDRS-III sub-score of axial and limb-akinetic-rigid items by the respective contralateral putaminal dopamine transporter signal.Additionally, both models included age and sex as covariables.

Survival analysis -Time until onset of levodopa-induced dyskinesia
To assess potential long-term effects of different resilience levels (0, +/-0.5SD and +/-1SD) more comprehensively, we performed Kaplan-Maier survival analyses to identify the resilience level-dependent time until the onset of levodopa-induced dyskinesia.
The occurrence of levodopa-induced dyskinesia was assessed by means of the MDS-UPDRS-III questionnaire (Question: "Were dyskinesias present?") and the MDS-UPDRS-IV questionnaire item 4.1 (Question: "Time spent with dyskinesias?").We assessed both questionnaires independently to consider potential differences between self-reported (MDS-UPDRS-IV) and rater-dependent (MDS-UPDRS-III) information.Analyses were performed at three different time intervals (84, 102, 156 months).For data availability at the different time points, see Supplementary Table 8.
The following open-source software versions and packages were used for the statistical analysis: RStudio version 1.3.959(R: A language and environment for statistical computing, 2020; R Core Team, R Foundation for Statistical Computing, Vienna, Austria. (https://www.R-project.org/),packages MASS 2 (version 7.3.51.5) , ppcor 3 (version 1.1)     and psych 4 (version 1.9.12.31).The table provides the unstandardized ß-coefficients, p-values and 95% confidence intervals (CI) for the three linear mixed models.The models were set up to estimate the resilience level dependent disease trajectories of the more and less affected axial LAR MDS-UPDRS-III-OFF sub-score as well as the total MDS-UPDRS-III-OFF score over seven years.On the upper part the included fixed effects are shown, while the middle part displays the estimates of the unstructured covariance matrix of the two random effects.Further, the bottom part shows the interpolation results for the years it would take for patients with high resilience to be on par with the motor performance levels of patients with low resilience.The table provides the unstandardized ß-coefficients, p-values and 95% confidence intervals (CI) for the three linear mixed models.The models were set up to estimate the resilience level-dependent disease trajectories of the more and less affected axial LAR MDS-UPDRS-III-OFF sub-scores as well as the total MDS-UPDRS-III-OFF score over seven years.In addition to the information provided in Supplementary

Python version 3.8 (Van
in the manuscript, is based on Williams tests or the comparison of r² values from evaluated regression models.For the Wiliams tests, Kendall's tau b was transformed in Pearson's r by using Kendall's formula 1 : r=sin(0.5πτ)All results regarding the Williams test are reported with one-tailed p-values given the clearly defined hypotheses.
mean putaminal dopamine transporter signal * MDS-UPDRS-III score vs. mean caudate nucleus dopamine transporter signal * MDS-UPDRS-III score axial MDS-UPDRS-III sub-score * mean putaminal dopamine transporter signal vs. LAR MDS-UPDRS-III sub-score * mean putaminal dopamine transporter signal vs. tremor MDS-UPDRS-III sub-score * mean putaminal dopamine transporter signal less affected axial LAR MDS-UPDRS-III sub-score ~ contralateral putaminal dopamine transporter signal, age, sex vs. more affected axial LAR MDS-UPDRS-III sub-score ~ contralateral putaminal dopamine transporter signal, age, sex Linear mixed modelling to assess longitudinal resilience effects Linear mixed model, including cognitive scores and medication information We addressed potential confounding effects of cognitive status and medication by incorporating LEDD and MoCA scores as continuous covariates in our mixed model analyses.The LEDD information was computed at each time point with an available MDS-UPDRS-III score.First, we filtered the "LEDD_concomitant_Medication_Log" file to obtain the prescribed medicines at the respective MDS-UPDRS-III assessment dates.Then, we added all levodopa doses and agonists multiplied by the respective conversion factors.Next, COMT inhibitors were accounted for by multiplying the daily dose by the inhibition factor and adding it to the respective dose.If missing data (e.g., unavailable prescription start dates) prevented an exact calculation of the LEDD, we treated the data at this time point as missing.Finally, like the MDS-UPDRS-III data, we smoothed the LEDD data by averaging scores over one year.
Rossum, G., & Drake Jr, F. L. (1995).Python reference manual.Centrum voor Wiskunde en Informatica Amsterdam) in form of a jupyter notebook5 (version 6.1.4),packages numpy6 (1.19.5), matplotlib7 (version 3.2.1),seaborn 8 (version 0.10.1),pandas 9 (version 1.3.5),and scipy.stats10(version 1.4.1).SupplementaryFigure 2 Correlation between baseline resilience values and daily physical activity from year one to seven Partial Spearman correlation between the baseline resilience estimates and the Physical Activity Scale for the Elderly score at year one till year seven follow-up, corrected for age and sex.Low, intermediate, and high resilience patients are indicated by blue-filled squares, grey-filled circles, and green-filled diamonds, respectively.The plots display 95% confidence intervals as error bars, estimated using bootstrapping with 1000 iterations.gre Supplementary Figure 3 -Voxel-wise grey matter volume group comparison considering dominant affected side as covariate Adding the dominant affected side as a covariate yielded clusters of higher grey matter volume in high-resilience patients in the same brain regions as in the previous analyses (i.e.postcentral gyrus (PoCGy), central operculum (CO), and exterior cerebellum (Cbe)).Notably, the cluster encompassing the left postcentral gyrus exhibited an increased extent, and an additional cluster emerged rostrally and ventrally to the pre-existing one in the right exterior cerebellum.No significant clusters of increased grey matter volume were found using the reversed contrast.All clusters shown here were significant at cluster-level after FWE-correction (p<0.05) with an initial p value set at p<0.001.intervals as error bars.MDS-UPDRS-III = Movement Disorder Society -Unified-253 Parkinson's-Disease-Rating-Scale motor-score, IV = motor complications in the entire Parkinson's disease cohort are summarized as mean ± standard deviation.MDS-UPDRS-III=Movement Disorder Society -Unified-Parkinson's-Disease-Rating-Scale motor-score; MoCA = Montreal-Cognitive-Assessment-Test; SD = standard deviation; SBR= Specific Binding Ratio; TIV=Total Intracranial Volume, *Patients with low (>0 residual value) or high resilience (<0 residual value) were identified and compared using Mann-Whitney-U for continuous and chi-square tests for categorical variables.

Table 1 ,
analyses listed in this table included the baseline Montreal Cognitive Assessment (MoCA) score and longitudinal levodopa equivalent daily dose as covariates.On the upper part the included fixed effects are shown, while the lower part displays the estimates of the unstructured covariance matrix of the two random effects.CI =